Despite aggressive treatment, the cure rate for patients with metastatic or advanced stage head and neck squamous cell carcinoma (HNSCC) is below 50% with recurrence rates ranging from 25-50%, depending on the disease site. Toxicity of the current treatment modalities frequently prevents treatment escalation and salvage therapies result in significant morbidity with minimal effect on outcome. Therefore novel treatment strategies are needed and there is renewed interest in immunotherapy for HNSCC. Photodynamic therapy (PDT) induces acute local and systemic inflammation that leads to enhanced anti-tumor immunity, which has potential to control distant disease. The overall hypothesis of this project is that PDT induction of acute inflammation reverses tumor-mediated immunosuppression and stimulates anti-tumor immunity. The ability of PDT and PDT-generated vaccines to enhance immune cell activation and recognition of HNSCC tumor cells will be examined with the intent of preventing or reducing HNSCC recurrence through activation of the immune system, which would significantly advance treatment of this disease. The focus of this project is to understand the mechanisms of PDT-enhancement of anti-tumor immunity with the long-term goal of expanding the use of PDT as an adjuvant for augmentation of anti-tumor immunity. To accomplish this goal the following hypotheses will be tested 1) PDT of HNSCC induces acute inflammation leading to increases in anti-tumor effector cells and decreases in regulatory T cells resulting in increased anti-tumor immunity; 2) activation of Th17 cells by PDT leads to enhanced secretion of IL17 that works in collaboration with IL1 to induce neutrophil mediated enhancement of DC activation within the TDLN resulting in stimulation of anti-tumor CD8+ T cells; and 3) PDT generated HNSCC tumor cell lysates can be used safely to augment anti-tumor immunity in HNSCC patients. The studies proposed in this project are compelling in that they have the potential to demonstrate that PDT of HNSCC is able to overcome tumor induced immunosuppression and activate anti- tumor immunity; thus providing rational for expanding the application of PDT beyond its current use as a local therapy. These studies are critical to the goals of this program project grant (PPG), as they will provide important information on the effect of the immune status of the patient on PDT efficacy in HNSCC, furthering the overall goal of moving PDT from a niche therapy to a standard of care for HNSCC though a deeper understanding of the mechanisms of PDT and the role the patient immune status plays in PDT efficacy. This Project will advance the field by determining the effect of PDT on tumor induced immunosuppression in patients, expanding the understanding of the role of PDT induced acute inflammation in anti-tumor immunity and long-term tumor growth control and beginning to assess the potential of PDT-generated anti-tumor vaccines.